The pancreas is a gland organ composed of two subclasses of tissue: the exocrine cells (acinar tissue) and the endocrine cells (islets of Langerhans). The exocrine cells produce the digestive enzymes that pass to the small intestine. The islet cells produce hormones which are involved in carbohydrate metabolism. Islets are composed of five cell types: α, β, δ, ε and PP cells which produce glucagon, insulin, somatostatin, ghrelin and pancreatic polypeptide, respectively. β cells secrete insulin in response to an increase in extracellular glucose concentration.
The first morphological signs of the primitive pancreas emerge as dorsal and ventral protrusions of the primitive gut epithelium at embryonic day (E) 9.5 in the mouse. Subsequently, all lineages defining the various pancreatic cell types, comprising endocrine islet and exocrine acinar and duct cells, are formed from a multipotent progenitor cell pool expressing the transcription factor Pdx1. The transcription factor Ngn3 is transiently expressed in a subset of the pancreas progenitor cells from E 9.5 to E 18.5 and initiates the differentiation program of all islet cells. It was demonstrated that Ngn3 is required for the specification of a common precursor for the five pancreatic endocrine cell types (α, β, δ, ε and PP) and mice lacking Ngn3 function fail to generate any pancreatic endocrine cells and die postnatally from diabetes (Gradwohl et al., 2000). The specification of different islet cell types and the completion of the differentiation process require the activation of transcription factors that are downstream of Ngn3. Among these regulatory factors NeuroD1, Pax4 and Nkx2.2 are direct targets of Ngn3.
Type 1 and type 2 diabetes are characterized by loss and dysfunction of β cells. Type 2 diabetes, which is the most common form, is associated with a gradual decline in sensitivity to insulin. Type 1 diabetes is a condition in which the body's immune cells attack β cells located in pancreatic islets, reducing or eliminating the body's ability to produce insulin. Treatment for type 1 diabetes is a lifelong commitment of monitoring blood glucose, exercising, dieting, and taking insulin. In some cases, individuals with type 2 diabetes similarly require insulin therapy. However, these approaches are sometimes insufficient to control blood glucose levels. Poorly controlled diabetes can lead to potentially fatal complications. Eyes, nerves and kidneys are particularly susceptible to the damage caused by poorly controlled type 1 or type 2 diabetes.
An alternative treatment for patients with type 1 diabetes is whole organ pancreatic transplant. Such a procedure offers the possibility of excellent glycemic control but patients are subjected to the adverse effects of immunosuppression and the risks of major surgery.
Recently great strides have been made in developing human islet transplantation in the treatment of diabetes. However, a large number of islets is required to achieve long-term insulin independence and two or far more donor organs are needed to accumulate enough islet cells for a single complete transplant. Thus, the lack of cadaveric human islets is a major obstacle in the widespread use of islets transplantation. Furthermore, with this procedure, immunosuppression is still necessary and the islets are often severely injured from storage conditions or transport time causing apoptosis of the insulin secreting β cells.
These limitations have given a high priority to efforts to stimulate the growth of new pancreatic islet tissue. As example, the patent application WO 2006/046923 proposes to treat pancreatic stem cells with retinoic acid to obtain pancreatic hormone-producing endocrine cells.
Nevertheless, there is still a strong need to provide methods for providing large number of β cells which could be used to treat diabetes by pancreatic islet transplantation or for promoting β cell maturation.